The regulation of body weight, and particularly body fat, in animals is a complex process having enormous implications for the health and well being of humans and other animals. Excess body weight and/or an excess of body fat relative to lean body mass has been associated with a wide range of health problems including coronary artery diseases, stroke, and diabetes.
It has been estimated that half of all Americans are overweight. Within the United States about 24% of men and 27% of women defined as mildly to severely obese. Individuals 20% over ideal weight guidelines are considered obese. Obesity is classified as mild (20-40% overweight), moderate (41-100% overweight), and severe ( greater than 100%) overweight. Severe obesity is relatively rare, affecting less than 0.5% of all obese individuals and about 0.1% of the total population.
Obesity is not just a problem for humans. Many animals also suffer adverse consequences related to obesity. For example, approximately 10 to 40% of cats receiving veterinary care have been reported to be overweight. Factors contributing to feline obesity include a sedentary lifestyle, confinement to indoors, and neutering. Obese cats have a greater risk for certain diseases including osteoarthritis, ligament injuries, perineal dermatitis, diabetes mellitus, cardiomyopathy, and urologic syndrome. Therefore, it is critical to maintain a healthy weight in order to minimize disease risk. See, U.S. Pat. No. 6,071,544.
Obesity in humans is treated by a variety of means ranging from surgical procedures (gastric bypass) for the severely obese to diet therapy, behavior modification, and medication for the mildly to moderately obese. Management of moderate and mild obesity is typically performed by the individual and commercial organizations which provide behavior modification programs and, in some cases, prepackaged diets. The medical community recommends that diet treatments be administered under medical supervision.
The range of treatments for obesity reflects the complexity of the processes involved in weight regulation and the current lack of understanding of these processes. Recent reports have even implicated viruses as a possible causative factor in obesity (U.S. News and World Report, Aug. 7, 2000). There are also numerous reports of possible genetic bases for a predisposition to obesity. Moll et al. have reported that, in many populations, obesity seems to be controlled by a few genetic loci (Moll et al. [1991] Am. J. Hum. Gene. 49:1243). In addition, human twin studies strongly suggest a substantial genetic basis in the control of body weight, with estimates of heritability of 80-90% (Simopoulos, A. P. and Childs, B., eds., 1989, in xe2x80x9cGenetic Variation and Nutrition in Obesityxe2x80x9d, World Review of Nutrition and Diabetes, 63, S. Karger, Basel, Switzerland; Bojeson, M., 1976, Acta. Paediatr. Scand. 65:279-287).
Recombinant agouti protein, an obesity gene product, stimulates Ca2+ influx in a variety of cells. Agouti also stimulates the expression and activity of fatty acid synthase (FAS), a key enzyme in de novo lipogenesis, and inhibits basal and agonist-stimulated lipolysis in human and murine adipocytes via a Ca2+ -dependent mechanism. These effects can be mimicked in the absence of agouti by either receptor or voltage-mediated Ca2+ channel activation and inhibited by a Ca2+ channel antagonist, such as nifedipine.
Recent data demonstrated that 1,25-dihydroxyvitamin D (1,25-(OH)2-D) causes a significant and sustained increase in intracellular calcium concentrations ([Ca2+]i) in primary cultured human adipocytes and a corresponding inhibition of lipolysis (Zemel et al. [2000] FASEB J. 14:1132-1138). Increasing dietary calcium suppresses [Ca2+]i, inhibits 1,25-(OH)2-D, and subsequently suppresses adiposity by stimulation of lipolysis and inhibition of lipogenesis. Consistent with these findings, increasing dietary calcium from 400 to 1000 mg/day resulted in a 4.9 kg reduction of body fat in humans over the course of one year (Zemel et al. [2000] FASEB J. 14:1132-1138). Dietary calcium can also attenuate the diet-induced development of adiposity and promote weight loss in established obesity (Shi, H. and Zemel, M. B. [2000] FASEB J. 555.3 (abstract)).
The subject invention provides materials and methods for treating or avoiding obesity in humans and other animals. Advantageously, the materials and methods of the subject invention can be used to easily and efficiently achieve weight loss and/or prevent weight gain. In a preferred embodiment, the obesity-control benefits of the subject invention are achieved by providing a diet high in calcium. In one aspect of the invention, individuals are maintained on a restricted caloric diet.
In a specific embodiment of the subject invention, calcium is provided in the form of dairy products. In yet another aspect of the invention, calcium is provided in the form of a dietary supplement, such as calcium carbonate, or vitamin supplements.
The subject invention also provides methods of stimulating lipolysis, inhibiting lipogenesis, and increasing the expression of white adipose tissue uncoupling protein 2 (UCP2). The subject invention also provides methods of increasing the core temperature of an individual as well as methods of diagnosing, treating, and/or monitoring obesity. Methods of suppressing [Ca2+]i levels in individuals are also provided.
The instant invention also provides methods of attenuating weight gain and adiposity in children and controlling weight gain in children by increasing the amounts of dietary calcium consumed by the children.